WO2002038561A1 - Indolylmaleimide derivatives as protein kinase c inhibitors - Google Patents

Indolylmaleimide derivatives as protein kinase c inhibitors Download PDF

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Publication number
WO2002038561A1
WO2002038561A1 PCT/EP2001/012785 EP0112785W WO0238561A1 WO 2002038561 A1 WO2002038561 A1 WO 2002038561A1 EP 0112785 W EP0112785 W EP 0112785W WO 0238561 A1 WO0238561 A1 WO 0238561A1
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WIPO (PCT)
Prior art keywords
alkyl
formula
compound
methyl
ring
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PCT/EP2001/012785
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English (en)
French (fr)
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WO2002038561A8 (en
Inventor
Rainer Albert
Nigel Graham Cooke
Sylvain Cottens
Claus Ehrhardt
Jean-Pierre Evenou
Richard Sedrani
Peter Von Matt
Jürgen Wagner
Gerhard Zenke
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Novartis Ag
Novartis Pharma Gmbh
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Priority to NZ525656A priority Critical patent/NZ525656A/xx
Priority to HK04100271.6A priority patent/HK1058789B/en
Priority to HU0301651A priority patent/HU228999B1/hu
Priority to AT01993604T priority patent/ATE445613T1/de
Priority to JP2002541095A priority patent/JP4234426B2/ja
Priority to AU2181002A priority patent/AU2181002A/xx
Priority to SK546-2003A priority patent/SK287919B6/sk
Priority to KR1020037005805A priority patent/KR100748386B1/ko
Priority to AU2002221810A priority patent/AU2002221810B2/en
Priority to IL15561801A priority patent/IL155618A0/xx
Priority to BRPI0115193A priority patent/BRPI0115193B1/pt
Priority to DK01993604T priority patent/DK1337527T3/da
Priority to CA002428133A priority patent/CA2428133C/en
Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Priority to DE60140201T priority patent/DE60140201D1/de
Priority to SI200130954T priority patent/SI1337527T1/sl
Priority to CZ2003-1266A priority patent/CZ307144B6/cs
Priority to MXPA03004037A priority patent/MXPA03004037A/es
Priority to EP01993604A priority patent/EP1337527B1/en
Publication of WO2002038561A1 publication Critical patent/WO2002038561A1/en
Priority to IL155618A priority patent/IL155618A/en
Priority to NO20032034A priority patent/NO327427B1/no
Publication of WO2002038561A8 publication Critical patent/WO2002038561A8/en
Priority to AU2005202387A priority patent/AU2005202387B2/en
Priority to NO20071232A priority patent/NO20071232L/no
Priority to IL182428A priority patent/IL182428A0/en

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Definitions

  • the present invention relates to indolylmaleimlde derivatives, process for their production and pharmaceutical compositions containing them.
  • R a is H; or Chalky! substituted by OH, NH 2 , or N(di-C ⁇ - 4 alkyl) 2 ;
  • R b is H; or C ⁇ alkyl
  • R is a radical of formula (a), (b), (c), (d), (e) or (f)
  • each of R 1f R 4 , R 7 , R a , Rn and R is OH; SH; a heterocyclic residue; NR ⁇ 6 R ⁇ 7 wherein each of R 16 and R 17 , independently, is H or C h alky! or R 16 and R ⁇ 7 form together with the nitrogen atom to which they are bound a heterocyclic residue; or a radical of formula ⁇
  • R X is a direct bond, O, S or NR 18 wherein R ⁇ 8 is H or Chalky!
  • R c is C ⁇ alkylene or C 1 . alkylene wherein one CH 2 is replaced by CR x R y wherein one of R x and R y is H and the other is CH 3 , each of R x and R y is CH 3 or R x and R y form together -CH 2 -CH 2 -, and
  • Y is bound to the terminal carbon atom and is selected from OH, a heterocyclic residue and -NR19R20 wherein each of R 19 and R 20 independently is H, C 3 . 6 cycloalkyl, C 3 - 6 cycloalkyl-C 1 - alkyl, aryl-C ⁇ alkyl or d.
  • Any alkyl or alkyl moiety in e.g. aikoxy may be linear or branched.
  • Halogen may be F, Cl, Br or I, preferably F or Cl.
  • Any aryl may be phenyl or naphthyl, preferably phenyl.
  • heterocyclic residue as Ri, R 4 , R 7 , R 8 , Rn, R ⁇ or Y or formed, respectively, by NR 6 R 17 or NR ⁇ 9 R 20 is meant a three to eight, preferably five to eight, membered saturated, unsaturated or aromatic heterocyclic ring comprising 1 or 2 heteroatoms, preferably selected from N, O and S, and optionally substituted.
  • Suitable examples include e.g. pyridyl, e.g. 3- or 4-pyridyl, piperidyl, e.g.
  • heterocyclic residue when substituted, this may be on one or more ring carbon atoms and/or on a ring nitrogen atom when present.
  • substituent on a ring carbon atom include e.g. C ⁇ - 4 alkyl e.g. CH 3 ;
  • C 3 . 6 cycloalkyl e.g. cyclopropyl, optionally further substituted by C ⁇ . alkyl; (C ⁇ wherein p is 1,2 or 3, preferably 1; CF 3 ; halogen; OH; NH 2 ; -CH 2 -NH 2 ; -CH 2 -OH; piperidin-1 -yl; or pyrrolidinyl.
  • a substituent on a ring nitrogen atom are e.g. d- 6 alkyl; acyl, e.g.
  • R'x-CO wherein R' x is H, d- 6 alkyl or phenyl optionally substituted by C h alky!, C ⁇ alkoxy or amino, e.g formyl; C 3 - 6 cycloalkyI; Cs-ecycloalkyl-d ⁇ alkyl; phenyl; phenyl-C 1 . 4 alkyl e.g. benzyl; a heterocyclic residue, e.g. as disclosed above, e.g. an aromatic heterocyclic residue comprising 1 or 2 nitrogen atoms; or a residue of formula ⁇
  • R 21 is d- alkylene or C 2 . alkylene interrupted by O and Y' is OH, NH 2 , NH(d- 4 alkyl) or.N(C ⁇ - 4 alkyl) 2 .
  • C 2 . 4 alkylene interrupted by O may be e.g. -CH2-CH2-O-CH 2 -CH2-.
  • the substituent on a cyclic nitrogen is a heterocyclic residue, it may be a five or six membered saturated, unsaturated or aromatic heterocyclic ring comprising 1 or 2 heteroatoms, preferably selected from N, O and S.
  • Examples include e.g. 3- or 4-pyridyl, piperidyl, e.g. piperidin-1 -yl, 3- or 4-piperidyl, homopiperidyl, piperazinyl, homopiperazinyl, pyrimidinyl, morpholin-4-yl, imidazolyl, imidazolidinyl, pyrrolyl or pyrrolidinyl,
  • R a is substituted d- 4 alkyl
  • the substituent is preferably on the terminal carbon atom.
  • ring A When ring A is substituted, it may be mono- or polysubstituted, preferably monosubstituted, the substituent(s) being selected from the group consisting of e.g. halogen, OH, d ⁇ alkoxy, e.g. OCH3, C 1 alkyl. e.g. CH 3 , NO 2 , CF 3 , NH 2 , NHC ⁇ alkyl, N(di-C ⁇ - alkyl) 2 and CN.
  • substituent(s) being selected from the group consisting of e.g. halogen, OH, d ⁇ alkoxy, e.g. OCH3, C 1 alkyl. e.g. CH 3 , NO 2 , CF 3 , NH 2 , NHC ⁇ alkyl, N(di-C ⁇ - alkyl) 2 and CN.
  • ring A may be a residue of formula
  • Ra is H; d- 4 alkyl; or halogen; and Re is OH; NO 2 ; NH 2 ; NHd- 4 alkyl; or N(di-d- 4 alkyl) 2 .
  • R d is in position 1 ; preferably R e is in position 3.
  • R c has a CH 2 replaced by CR x R y , it is preferably the CH 2 bearing Y.
  • heterocyclic residue as Ri, R 4 , R 7 , R 8 , Rn, R ⁇ or Y or formed, respectively, by NR 16 Ri7 or NR 19 R 2 o include e.g. a residue of formula ( ⁇ )
  • ring D is a 5, 6 or 7 membered saturated, unsaturated or aromatic ring
  • a preferred residue of formula ( ⁇ ) is one wherein the ring D forms a 1 ,4-piperazinyl ring optionally C- and/or N-substituted as indicated.
  • a residue of formula ( ⁇ ) are e.g. 3- or 4- pyridyl; piperidin-1 -yl; 1 -N-(C ⁇ - alkyl)- or -( ⁇ 3 hydroxy-d- alkyl)-3-piperidyl; morpholin-4-yl; imidazolyl; pyrrolidinyl; 1-piperazinyl; 2-d- 4 alkyl- or -C 3 . 6 cycloalkyl-1 -piperazinyl ;3-C ⁇ . 4 alkyl- or -C 3 . 6 cycloalkyl-1- piperazinyl; 2,2- or 3,5- or 2,5- or 2,6-di(C 1 .
  • alkyl)-1 -piperazinyl 1,3-bis(C alkyl)-1 -piperazinyl; 3,4,5-tri-(C alkyl)-1 - piperazinyl; 4-N-(d. alkyl)- or -( ⁇ -hydroxy-C ⁇ - 4 alkyl)- or -( ⁇ -dimethylamino-d- 4 alkyl)-1 - piperazinyl; 4-N-pyridin-4-yl-1 -piperazinyl; 4-N-phenyl- or -C 3 . 6 cycloalkyl-1 -piperazinyl; 4-N- (d- 4 alkyl)- or -(cohydroxy-C 1 . 4 alkyl)-3-C 1 .
  • the compounds of formula I may exist in free form or in salt form, e.g. addition salts with e.g. organic or inorganic acids, for example, hydrochloric acid, acetic acid, when R ⁇ R , R , R 8 , Rn or R 14 and/or R 2 , R 3 , R 5 , R 6 , Rg, Rio.
  • R12, R1 3 or R 15 comprises an optionally substituted amino group or a heterocyclic residue which can form acid addition salts.
  • the compounds of formula I may exist in the form of optical isomers, racemates or diastereoisomers.
  • a ring carbon atom bearing a substituent in the heterocyclic residue as Ri, R 4 , R 7 , R 8 , Rn, R 14 or Y or formed, respectively, by NR ⁇ 6 R ⁇ 7 or NR ⁇ 9 R 20) is asymmetric and may have the D- or L- configuration.
  • the present invention embraces all enantiomers and their mixtures. Similar considerations apply in relation to starting materials exhibiting asymetric carbon atoms as mentioned.
  • R a is H or CH 3 ;
  • R b is H
  • Ring A is unsubstituted; or is substituted by methyl in position 7; 4.
  • Preferred heterocyclic residue as formed by NR 16 R 17 is e.g. piperazin-1-yl optionally N- substituted, e.g. by d- 4 alkyl, o hydroxy-C ⁇ - 4 alkyl, ⁇ >-dimethylamino-C ⁇ - alkyl, C 5 - ecycloalkyl, C 1 - 4 alkyl-C 5 . 6 cycloalkyl, an aromatic heterocyclic residue comprising 1 or 2 nitrogen atoms, e.g.
  • pyridyl or pyrimidin-2-yl or a residue of formula ⁇ as defined above and/or optionally C-substituted, e.g. by CH 3 e.g. in positions 2, and/or 3 and/or 5 and/or
  • piperidin-1 -yl optionally C- substituted, e.g. in position 4, by NH 2 , -CH 2 -NH 2 or piperidin-1 -yl, or in position 3, e.g. by OH or NH 2 ; or pyrrolidinyl optionally C-substituted in position 3 by OH or NH 2 ;
  • R 18 is H or CH 3 ;
  • R c is d. 4 alkylene or C ⁇ - alkylene wherein the terminal CH 2 is replaced by CR x R y wherein R x and R y form together -CH 2 -CH 2 -;
  • the radical of formula ( ) is -O-CH 2 -CH 2 -Y;
  • R 19 and R 20 is H, C ⁇ - 4 alkyl, e.g. methyl, d- 4 alkyl substituted on the terminal carbon atom by OH, e.g. -CH 2 -CH 2 -OH, or cyclopropyl;
  • Preferred heterocyclic residue as formed by NR 19 R 20 is e.g. piperazin-1 -yl optionally N- substituted by C 1 . alkyl or a residue of formula ⁇ ; piperidin-1 -yl; 1-(C ⁇ . 4 alkyl)-piperidin-3- yl; 3- or 4-pyridyl; imidazolyl; pyrrolidinyl; or morpholin-4-yl;
  • R R 4 , R 7 , R 8 , R t1 or R 14 independently, is 1 -N-methyl-piperidin-4-yl; 4-methyl-piperazin-1 -yl; 4-methyl-1 -homopiperazinyl; 4-(2-hydroxyethyl)-piperazin-1 -yl; or -X'-d, 2 or 3 -alkylene-NR 19 R 20 wherein X' is a direct bond, O or NH;
  • each of R 2 and R 3 is H or one of R 2 and R 3 is H and the other is F, Cl, CH 3) OH, OCH 3 or CF 3 ;
  • R 2 is OH
  • each of R 5 and R 6 is H or one of R 5 and R 6 is H and the other is F, Cl, CH 3 , OCH 3 or CF 3 ;
  • R is a radical of formula ( ⁇ ) or NR ⁇ 6 R ⁇ 7 ;
  • each of R 9 and Rio is H or one of R 9 and R 10 is H and the other is F, Cl, CH 3 , OCH 3 or CF 3 ; preferably R 10 is H and R 9 is in position 5, 6, 7 or 8, preferably in position 6;
  • each of R 12 and R 13 is H; 18.
  • R ⁇ 5 is H, CH 3 or Cl, e.g. in position 5 or 6;
  • R' 5 is H or CH 3 , e.g. in position 5, preferably H;
  • R is a radical of formula (d), (e) or (f).
  • the present invention also includes a process for the preparation of a compound of formula
  • Process steps a) and (b) may conveniently be effected in the presence of a strong base, e.g. t-BuOK.
  • a strong base e.g. t-BuOK.
  • compounds of formula III or V comprising an OH group which should not participate to the reaction are used, such OH group is in protected form.
  • the OH-protecting group may be removed according to methods known in the art at the end of condensation step a) or b).
  • Process step c) may be carried out according to known methods: for example when R R 4 , R 7 , R 8 , Rn or R 14 comprises a final OH group, this OH group may be replaced by the desired -NR 16 R 17 or -NR 19 R 20 .
  • Compounds of formula ll may be prepared by reacting the corresponding indol compound with an oxalyl halogenide, e.g. chloride, or with a monoalkyl oxalyl chloride under basic conditions, e.g. as disclosed in Example 28.
  • an oxalyl halogenide e.g. chloride
  • a monoalkyl oxalyl chloride under basic conditions, e.g. as disclosed in Example 28.
  • R" - CO - CO - OCH 3 V
  • each of R' or R" is respectively a radical of formula (a), (b), (c), (d), (e) or (f), each of which comprising a leaving group, e.g. halogen, in place of Ri, R , R 7 , R 8 , Rn or R 14 .
  • compounds of formula III wherein R is a radical of formula (a), (b) or (c), R 1 f R or R 7 being a radical of formula ( ), may be prepared in accordance with known methods by reacting a compound of formula III' wherein R' is respectively a radical of formula (a), (b) or (c), each of which comprising OH in place of R ⁇ R 4 or R 7 , with a compound of formula X a -X- R c -Y wherein X a is a leaving group, e.g. Cl, and X, R c or Y are as defined above.
  • R i2 and R 13 are as defined above and X a is a leaving group, e.g. halogen, and with a compound of formula VI
  • R 9 , Rio, R 15 and R' ⁇ 5 are as defined above and X a is a leaving group, e.g. halogen, and with a compound of formula VI'
  • 3-(1.H-lndol-3-yl)-4-[3-(2-methanesulfonyloxy-ethoxy)-5-hydroxy-phenyl]-pyrrole-2,5-dione, used as starting material, may be prepared as follows: a) [3-(2-Triisopropylsilyloxy-ethoxy)-5-hydroxy-phenyl]-acetic acid methyl ester A mixture of 9.39 g (51.5 mmol) of (3,5-dihydroxy-phenyl)-acetic acid methyl ester (prepared according to U. Eder, G. Sauer, G. Haffer, G. Neef, R.
  • Ri and R 2 are as defined in Table 1 , may be prepared by following the procedure of Example 1 but using the appropriate starting materials. Starting materials which do not comprise a O ⁇ substituent will be prepared without the protecting steps as indicated in Example 1.
  • 3-(7.H-lndol-3-yl)-4-[3-(2-methanesulfonyloxy-ethoxy)-naphthalen-1-yl]-pyrrole-2,5-dione, used as starting materials may be prepared as follows: a) 1 -Bromo-3-(2-triisopropylsilyloxy-ethoxy)-naphtalene
  • reaction mixture is allowed to cool to RT and is filtered.
  • the filtrate is concentrated under reduced pressure.
  • product is then crystallized from diethylether, filtered and washed with one portion of diethylether, two portions of water and another portion of diethylether. This procedure affords above title compound as red-orange crystals.
  • R 3 is as defined in Table 2
  • Table 2 wherein R 3 is as defined in Table 2, may be prepared by following the procedure of Example 28 but using the appropriate starting materials. Table 2
  • Examples 48 and 52 which are racemates may also be prepared in the form of pure cis or trans enantiomers using the corresponding cis or trans starting materials.
  • step b) 8-bromo-tetralin-6-yl acetate Compound of step a) (7.28 g, 28.75 mmol) is dissolved in CH 2 CI 2 (60 ml). 2 equivalents m- chloroperbenzoic acid (11.7 g, FLUKA 25800, 70%) is added at RT and after addition of sodium sulfate (5 g) the reaction mixture is treated with trifluoromethanesulfonic acid (250 ⁇ l, 2.88 mmol). The reaction is kept at RT for 16 hours.
  • step b) Compound of step b) (6.1 g, 22.66 mmol) is added to MeOH (200 ml) at RT. 1N sodium methoxide in methanol (22.7 ml) is stirred for 15 min. Amberlite IR-120 (H + -form) is added to the mixture until the reaction mixture becomes neutral. The ion exchanger is filtered off, the solvent is evaporated and the crude product is isolated without any further purification as a pale yellow solid. d) 2-(2-t.butoxy-ethoxy)-4-bromo-5,6,7,8-tetrahydro-naphthalene Compound of step c) (2.8 g, 12.33 mmol) is added to THF (100ml) at RT.
  • Triphenyl- phosphine (16.82 g, 64.13 mmol) and (after 10 minutes) diisopropylazodicarboxylate (11.66 ml, 59.2 mmol) are added and the mixture is stirred for 14 hours. The solvent is removed and the residue is purified on silica gel using cyclohexane (100%) to cyclohexane/- methylene chloride (1/1) as mobile phase, obtaining the product as a pale yellow solid.
  • step d) 3-(2-t.butoxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1 -yl-oxo-acetic acid methyl ester
  • compound of step d) (2.61 g, 7.96 mmol) is dissolved in dry THF (70 ml) at RT and cooled down to -70° C.
  • Butyllithium (5.5 ml, 8.76 mmol, 1.6 M in hexane) is added dropwise to the reaction mixture under inert atmosphere (argon).
  • a solution of dimethyl oxalate (1.9 g, 15.92 mmol) in 5 ml dry THF is added to the reaction mixture and the reaction is warmed up to RT.
  • Example 55A 3-(1. W.-lndol-3-yl)-4-[3-(4-methyl-piperazin-1 -yl)-5,6,7,8-tetrahydro- naphthalen-1-yl]-pyrrole-2,5-dione
  • the title compound is prepared by condensing 2-[3-(4-methyl-piperazin-1 -yl)-5,6,7,8- tetrahydro-naphthalen-1-yl]-acetamide with (1.r/.-indol-3-yl)-oxo-acetic acid methyl ester in analogy to example 53 (step f).
  • MH + 441 (ES + )
  • Example 55B 3-(1-Methyl-1.H.-indol-3-yl)-4-[3-(4-methyl-piperazin-1-yl)-5,6,7,8- tetrahydro-naphthalen-1-yl]-pyrrole-2,5-dione
  • step b) (3-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1 -yl)-acetic acid ethyl ester DL-Methionine (1.11 g, 7.5 mmol) and compound of step b) is dissolved in methanesulfonic acid (9 ml) and kept at RT over night. The reaction is poured into a ice-cold saturated NaCI solution and extracted 3 times with methylene chloride. The organic layer is dried, concentrated and purified on silica gel (methylene chloride/methanol 95/5) affording the pure compound.
  • ⁇ /,/V-dimethylaniline 7.8 mL, 1.0 eq.
  • the mixture is heated to 110°C and kept at reflux for 35 h.
  • the solution is cooled to RT and poured onto an ice- water mixture.
  • the precipitate is filtered off and washed with ⁇ 2 O.
  • the solid is redissolved in AcOEt and washed with H 2 O and brine.
  • R 1f R 5 , R 6 and R 7 are as defined in Table 3 below, may be prepared by following the procedure of Example 56 but using the appropriate starting materials. The compounds may also be converted into the acetate salt as disclosed for the compound of Example 56, where appropriate. Table 3
  • Example 77 which is a racemate may also be prepared in the form of pure cis or trans enantiomer using the corresponding cis or trans starting materials.
  • Compounds of Examples 116 and 117 may also be prepared as a racemate or in the corresponding S or R isomer form.
  • R, Ri and R 2 are as defined in Table 4 below, may be prepared by following the procedure of Example 56 but using the appropriately substituted (1.r/.-indol-3-yl)-oxo-acetic acid methyl ester.
  • the compounds are prepared by following the procedure of Example 56 but using the appropriately substituted (1.f/.-indol-3-yl)-oxo-acetic acid methyl ester.
  • Example 149A Example 149B M + 486 M + 500
  • R, R and R 2 are as defined in Table 5 below, may be prepared by following the procedure of Example 56 but using the appropriately substituted (1 ,K-indol-3-yl)-oxo-acetic acid methyl ester.
  • 2-(2-chloro-quinolin-4-yl)-acetic acid methyl ester may be prepared as disclosed in EP- A1 - 0 364327 and Indian J. Chem. 1994, 33B, 747-751.
  • 2-(2-chloro-quinolin-4-yl)-acetic acid methyl ester (100 mg, 0.42 mmol) is suspended in 28% NH 4 OH (2.0 mL). The mixture is stirred at RT overnight. The solvent is evaporated to afford 2-(2-chloro-quinolin-4-yl)-acetamide as a solid.
  • 2-(2-chloro-quinolin-4-yl)-acetamide (500 mg, 2.27 mmol) is dissolved in 1-methyl-2- pyrrolidinone (3.0 mL). N-methylpiperazin (1.3 mL, 5 eq.) is added and the reaction is stirred at 80°C for 48 h. AcOEt (20 mL) is added and the precipitate is purified by FCC (AcOEt/EtOH/28% NH 4 OH 80:18:1) to afford 2-[2-(4-methyl-piperazin-1-yl)-quinolin-4-yl]- acetamide as a solid.
  • R 8 and R 9 are as defined in Table 6 below, may be prepared by following the procedure of Example 162 or 163 but using the appropriate starting materials.
  • Example 181 3-( f .H--lndol-3-yl)-4-[3-(4-methyl-piperazin-1 -yl)-isoquinolin-1 -yl]- pyrrole-2,5-dione
  • the organic phase is separated, dried with Na 2 SO 4 , concentrated and purified on silica gel using methylene chloride/methanol/acetic acid 50% (9/1/0.25) as mobile phase.
  • the fractions with the title compound are collected and extracted with aqueous NaHCO 3 solution (6%).
  • the organic phase is separated, dried with Na 2 SO 4 , and concentrated to give pure title compound as orange powder.
  • 3-(3-Chloro-isoquinolin-1 -yl)-4-(1.H-indol-3-yl)-pyrrole-2,5-dione, used as starting material, may be prepared as follows: a) (3-chloro-isoquinolin-1 -yl) acetic acid ethyl ester may be prepared as disclosed by T. Kametani et al. in Chem. Pharm. Bull., 15(5), 704 (1967). b) (3-chloro-isoquinolin-1-yl)-acetic acid ethyl ester (2.5 g, 10 mmol) is dissolved in 4N NHs/MeOH (50 ml).
  • Example 182 3-(1 -Methyl-1./f,-indol-3-yl)-4-[3-(4-methyl-piperazin-1 -yl)-isoquinolin-1 - yl]-pyrrole-2,5-dione
  • 2-[3-(4-Methyl-piperazin-1-yl)-isoquinolin-1-yl]-acetamide, used as starting material, may be prepared as follows: a) (3-Chloro-isoquinolin-1-yl)-acetic acid ethyl ester (13 g, 50 mmol) is dissolved in dioxane (150 ml) under argon.
  • R a , R c , R 8 and R 9 are as defined in Table 7 below, may be prepared by following the procedure of Example 181 but using the appropriate starting materials.
  • the compounds of formula I in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, e.g. inhibiting Protein Kinase C (PKC), e.g. PKC isoforms like oc, ⁇ , ⁇ , ⁇ , ⁇ or ⁇ activity, inhibiting T-cell activation and proliferation, e.g. by inhibiting production by T-cells or cytokines, e,g, IL-2, by inhibiting the proliferative response of T-cells to cytokines, e.g. IL-2, e.g. as indicated in in vitro and in vivo tests and are therefore indicated for therapy.
  • PKC Protein Kinase C
  • the compounds of formula I are tested for their activity on different PKC isoforms according to a published method (D. Geiges et al. Biochem. Pharmacol. 1997;53:865-875)
  • the assay is performed in a 96-well polypropylene microtiterplate (Costar 3794) that has been previously siliconized with Sigmacote (Sigma SL-2).
  • the reaction mixture (50 ⁇ l) contains 10 ⁇ l of the relevant PKC isozyme together with 25 ⁇ l of the test compound and 15 ⁇ l of a mix solution that contains 200 ⁇ g/ml protamine sulfate, 10 mM Mg(NO 3 ) 2 , 10 ⁇ M ATP (Boehringer 519987) and 3750 Bq of 33 P-ATP (Hartmann Analytic SFC301 , 110TBq/mmol) in 20 mM Tris-buffer pH 7.4 + 0.1% BSA. Incubation is performed for 15 min at 32°C in a microtiterplate shaking incubator (Biolabo Scientific Instruments). Reaction is stopped by adding 10 ⁇ l of 0.5 M Na 2 EDTA, pH 7.4.
  • IC 50 measurement is performed on a routine basis by incubating a serial dilution of inhibitor at concentrations ranging between 1-1000 ⁇ M according to the method described above. IC 50 value are calculated from the graph by sigmoidal curve fitting.
  • Human recombinant PKC ⁇ was obtained from PanVera and is used under the assay conditions as described under Section AJ above.
  • Compound of Example 85 inhibits PKC ⁇ in this assay with an IC 50 of 50 ⁇ 9nM.
  • the assay is performed with Jurkat cells transfected with a human interleukin-2 promoter/reporter gene construct as described by Baumann G et al. in Transplant.Proc. 1992;24:43-8, the ⁇ -galactosidase reporter gene being replaced by the luciferase gene (de Wet J., et al., Mol. Cell Biol. 1987, 7(2), 725-737).
  • Cells are stimulated by solid phase- coupled antibodies or phorbol myristate acetate (PMA) and the Ca** ionophore ionomycin as follows.
  • Microlite TM1 microtiter plates (Dynatech) are coated with 3 ⁇ g/ml goat anti-mouse IgG Fc antibodies (Jackson) in 55 ⁇ l phosphate- buffered saline (PBS) per well for three hours at room temperature. Plates are blocked after removing the antibodies by incubation with 2% bovine serum albumin (BSA) in PBS (300 ⁇ l per well) for 2 hours at room temperature.
  • BSA bovine serum albumin
  • test compounds in duplicates in assay medium (RPM1 1640/10% fetal calf serum (FCS) containing 50 ⁇ M 2-mercaptoethanol, 100 units/ml penicillin and 100 ⁇ g/ml streptomycin) are prepared in separate plates, mixed with transfected Jurkat cells (clone K22290_H23) and incubated for 30 minutes at 37°C in 5% CO 2 . 100 ⁇ l of this mixture containing 1x10 5 cells are then transferred to the antibody- coated assay plates. In parallel 100 ⁇ l are incubated with 40 ng/ml PMA and 2 ⁇ M ionomycin.
  • FCS transfected Jurkat cells
  • the level of luciferase is determined by bioluminescence measurement.
  • the plates are centrifuged for 10 min at 500 g and the supernatant is removed by flicking.
  • Lysis buffer containing 25 mM Tris-phosphate, pH 7.8, 2 mM DTT, 2 mM 1.2-diaminocyclohexane-N,N,N',N-tetraacetic acid, 10 % (v/v) glycerol and 1 % (v/v) Triton X-100 is added (20 ⁇ l per well). The plates are incubated at room temperature for 10 minutes under constant shaking.
  • Luciferase activity is assessed with a bioluminescence reader (Labsystem, Helsinki, Finland) after automatic addition of 50 ⁇ l per well luciferase reaction buffer containing 20 mM Tricine, 1.07 mM (MgCO 3 ) 4 Mg(OH) 2 x5H 2 O, 2.67 mM MgSO 4 , 0J mM EDTA, 33.3 mM DTT, 270 ⁇ M coenzyme A, 470 ⁇ M luciferin (Chemie Brunschwig AG), 530 ⁇ M ATP, pH 7.8.
  • Lag time is 0.5 seconds, total measuring time is 1 or 2 seconds.
  • Low control values are light units from anti-T cell receptor- or PMA-stimulated cells
  • high controls are from anti-T cell receptor/anti- CD28- or PMA/ionomycin-stimulated cells without any test sample.
  • Low controls are subtracted from all values.
  • the inhibition obtained in the presence of a test compound is calculated as percent inhibition of the high control.
  • the concentration of test compounds resulting in 50% inhibition (IC 50 ) is determined from the dose-response curves.
  • compounds of formula I inhibit anti-T cell receptor/anti-CD28 and PMA/ionomycin stimulated Jurkat cells with an IC 50 ⁇ 1 ⁇ M.
  • Compound of Example 56 has an IC 50 of 42 ⁇ 12 nM in this assay.
  • MLR Allogeneic Mixed Lymphocyte Reaction
  • spleen cells from CBA and BALB/c mice (1.6 x 10 5 cells from each strain per well in flat bottom tissue culture microtiter plates, 3.2 x 10 5 in total) are incubated in RPMI medium containing 10% FCS, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin (Gibco BRL, Basel, Switzerland), 50 ⁇ M 2-mercaptoethanol (Fluka, Buchs, Switzerland) and serially diluted compounds. Seven three-fold dilution steps in duplicates per test compound are performed. After four days of incubation 1 ⁇ Ci 3 H-thymidine is added.
  • the strain combination used Male Lewis (RT 1 haplotype) and BN (RT 1 haplotype).
  • the animals are anaesthetised using inhalational isofluorane. Following heparinisation of the donor rat through the abdominal inferior vena cava with simultaneous exsanguination via the aorta, the chest is opened and the heart rapidly cooled. The aorta is ligated and divided distal to the first branch and the brachiocephalic trunk is divided at the first bifurcation. The left pulmonary artery is ligated and divided and the right side divided but left open. All other vessels are dissected free, ligated and divided and the donor heart is removed into iced saline.
  • the recipient is prepared by dissection and cross-clamping of the infra-renal abdominal aorta and vena cava.
  • the graft is implanted with end-to-side anastomoses, using 10/0 monofilament suture, between the donor brachiocephalic trunk and the recipient aorta and the donor right pulmonary artery to the recipient vena cava.
  • the clamps are removed, the graft tethered retroabdominally, the abdominal contents washed with warm saline and the animal is closed and allowed to recover under a heating lamp.
  • Graft survival is monitored by daily palpation of the beating donor heart through the abdominal wall. Rejection is considered to be complete when heart beat stops. Increases of graft survival are obtained in animals treated with a compound of formula I administered orally at a daily dose of 1 to 30 mg/kg. Thus compound of Example 100 significantly increases the graft survival when administered at a dose of 30 mg/kg/day.
  • the compounds of formula I are, therefore, useful in the treatment and/or prevention of diseases or disorders mediated by T lymphocytes and/or PKC, e.g. acute or chronic rejection of organ or tissue allo- or xenografts, atherosclerosis, vascular occlusion due to vacular injury such as angioplasty, restenosis, hypertension, heart failure, chronic obstructive pulmonary disease, CNS diseases such as Alzheimer disease or amyotrophic lateral sclerosis, cancer, infectious diseases such as AIDS, septic shock or adult respiratory distress syndrome, ischemia/reperfusion injury e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, or traumatic shock.
  • diseases or disorders mediated by T lymphocytes and/or PKC e.g. acute or chronic rejection of organ or tissue allo- or xenografts, atherosclerosis, vascular occlusion due to vacular injury such as angioplasty, restenosis, hypertension
  • the compounds of formula I are also useful in the treatment and/or prevention of T-cell mediated acute or chronic inflammatory diseases or disorders or autoimmune diseases e.g. rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or II and the disorders associated therewith, respiratory diseases such as asthma or inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically-mediated disorders or illnesses, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis), inflammatory eye diseases, e.g.
  • Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis For the above uses the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0J to about 100 mg/kg body weight.
  • An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 2000 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.
  • the compounds of formula I may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form.
  • Pharmaceutical compositions comprising a compound of formula I in free form or in pharmaceutically acceptable salt form in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
  • Unit dosage forms for oral administration contain, for example, from about OJ mg to about 500 mg of active substance.
  • Topical administration is e.g. to the skin.
  • a further form of topical administration is to the eye.
  • the compounds of formula I may be administered in free form or in pharmaceutically acceptable salt form e.g. as indicated above.
  • Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
  • the present invention further provides:
  • a method for preventing or treating disorders or diseases mediated by T lymphocytes and/or PKC, e.g. such as indicated above, in a subject in need of such treatment comprises administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
  • a method for preventing or treating acute or chronic transplant rejection or T-cell mediated inflammatory or autoimmune diseases, e.g. as indicated above, in a subject in need of such treatment comprises administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
  • a compound of formula I in free form or in a pharmaceutically acceptable salt form for use as a pharmaceutical, e.g. in any of the methods as indicated under 1 J and 1.2 above.
  • a pharmaceutical composition e.g. for use in any of the methods as in 1 J and 1.2 above comprising a compound of formula I in free form or pharmaceutically acceptable salt form in association with a pharmaceutically acceptable diluent or carrier therefor.
  • Compounds of formula I may be administered as the sole active ingredient or together with other drugs in immunomodulating regimens or other anti-inflammatory agents e.g. for the treatment or prevention of allo- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders.
  • they may be used in combination with cyclosporines, or ascomycines or their immunosuppressive analogs or derivatives, e.g. cyclosporin A, cyclosporin G, FK-506, ABT-281 , ASM 981 ; an mTOR inhibitor, e.g.
  • rapamycin 40-O-(2- hydroxy)ethyl-rapamycin etc.
  • corticosteroids cyclophosphamide
  • azathioprene methotrexate
  • methotrexate an accelerating lymphocyte homing agent, e.g.
  • FTY 720 leflunomide or analogs thereof; mizoribine; mycophenolic acid; mycophenolate mofetil; 15- deoxyspergualine or analogs thereof; immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD 11a CD18, CD7, CD25, CD 27, B7, CD40, CD45, CD58, CD 137, ICOS, CD150 (SLAM), OX40, 4-1 BB or their ligands, e.g. CD154; or other im unomodulatory compounds, e.g.
  • immunosuppressive monoclonal antibodies e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD 11a CD18, CD7, CD25, CD 27, B7, CD40, CD45, CD58, CD 137, ICOS, CD150 (SLAM), OX40, 4
  • a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y, or other adhesion molecule inhibitors, e.g. mAbs or low molecular weight inhibitors including LFA-1 antagonists, Selectin antagonists and VLA-4 antagonists.
  • Compounds of formula I may also be administered together with an antiproliferative drug, e.g. a chemotherapeutic drug, e.g. in cancer treatment, or with an anti-diabetic drug in diabetes therapy.
  • a method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of an inhibitor of PKC and of T-cell activation and proliferation, e.g. a compound of formula I in free form or in pharmaceutically acceptable salt form, and a second drug substance, said second drug substance being an immunosuppressant, immunomodulatory, anti-inflammatory, antiproliferative or anti-diabetic drug, e.g. as indicated above.
  • a therapeutic combination e.g. a kit, comprising a) an inhibitor of PKC and of T-cell activation and proliferation, e.g. a compound of formula I in free form or in pharmaceutically acceptable salt form, and b) at least one second agent selected from an immunosuppressant, immunomodulatory, anti-inflammatory, antiproliferative and anti- diabetic drug.
  • Component a) and component b) may be used concomitantly or in sequence.
  • the kit may comprise instructions for its administration.
  • an inhibitor of PKC and of T-cell activation and proliferation e.g. a compound of formula I
  • other immunosuppressive/immunomodulatory, anti-inflammatory, antiproliferative or anti-diabetic therapy e.g. for preventing or treating acute or chronic graft rejection or inflammatory or autoimmune disorders as hereinabove specified
  • dosages of the co-administered immunosuppressant, immunomodulatory, anti- inflammatory, antiproliferative or anti-diabetic compound will of course vary depending on the type of co-drug employed, e.g. whether it is a steroid or a cyclosporine, on the specific drug employed, on the condition being treated and so forth.
  • a preferred compound according to the invention is e.g. the compound of Example 56.

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PCT/EP2001/012785 2000-11-07 2001-11-05 Indolylmaleimide derivatives as protein kinase c inhibitors WO2002038561A1 (en)

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Application Number Priority Date Filing Date Title
CA002428133A CA2428133C (en) 2000-11-07 2001-11-05 Indolylmaleimide derivatives as protein kinase c inhibitors
HU0301651A HU228999B1 (en) 2000-11-07 2001-11-05 Indolylmaleimide derivatives
AT01993604T ATE445613T1 (de) 2000-11-07 2001-11-05 Indolylmaleimidderivative als proteinkinase-c- inhibitoren
JP2002541095A JP4234426B2 (ja) 2000-11-07 2001-11-05 プロテインキナーゼｃインヒビターとしてのインドリルマレイミド誘導体
AU2181002A AU2181002A (en) 2000-11-07 2001-11-05 Indolylmaleimide derivatives as protein kinase c inhibitors
SK546-2003A SK287919B6 (sk) 2000-11-07 2001-11-05 Indolylmaleimide derivatives, method for the preparation thereof and pharmaceutical composition comprising same
KR1020037005805A KR100748386B1 (ko) 2000-11-07 2001-11-05 단백질 키나제 ｃ 억제제로서의 인돌릴말레이미드 유도체
AU2002221810A AU2002221810B2 (en) 2000-11-07 2001-11-05 Indolylmaleimide derivatives as protein kinase C inhibitors
HK04100271.6A HK1058789B (en) 2000-11-07 2001-11-05 Indolylmaleimide derivatives as protein kinase c inhibitors
BRPI0115193A BRPI0115193B1 (pt) 2000-11-07 2001-11-05 derivados de indolilmaleimida, processo para preparação dos mesmos, bem como composição farmacêutica que os compreende
DK01993604T DK1337527T3 (da) 2000-11-07 2001-11-05 Indolylmaleinimidderivater som proteinkinase C-inhibitorer
NZ525656A NZ525656A (en) 2000-11-07 2001-11-05 Indolylmaleimide derivatives as protein kinase C inhibitors
IL15561801A IL155618A0 (en) 2000-11-07 2001-11-05 Indolylmaleimide derivatives as protein kinase c inhibitors
EP01993604A EP1337527B1 (en) 2000-11-07 2001-11-05 Indolylmaleimide derivatives as protein kinase c inhibitors
SI200130954T SI1337527T1 (sl) 2000-11-07 2001-11-05 Derivati indolilmaleimida kot inhibitorji protein-kinaze C
CZ2003-1266A CZ307144B6 (cs) 2000-11-07 2001-11-05 Indolylmaleinimidová sloučenina, způsob její přípravy, její použití jako léčivo a farmaceutická kompozice obsahující tuto sloučeninu
MXPA03004037A MXPA03004037A (es) 2000-11-07 2001-11-05 Derivados de indolilmaleimida como inhibidores de proteina de cinasa c.
DE60140201T DE60140201D1 (en) 2000-11-07 2001-11-05 Indolylmaleimidderivative als proteinkinase-c-inhibitoren
IL155618A IL155618A (en) 2000-11-07 2003-04-28 Derivatives of indolyl malayamide as inhibitors of protein-kinase C
NO20032034A NO327427B1 (no) 2000-11-07 2003-05-06 Indolylmaleimidderivater, farmasoytiske sammensetninger samt anvendelser av slike.
AU2005202387A AU2005202387B2 (en) 2000-11-07 2005-06-01 Indolylmaleimide derivatives as protein kinase C inhibitors
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